Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
J Med Chem. 2012 Nov 26;55(22):9891-9. doi: 10.1021/jm301098e. Epub 2012 Oct 23.
The incidence of malignant melanoma has dramatically increased in recent years thus requiring the need for improved therapeutic strategies. In our efforts to design selective histone deactylase inhibitors (HDACI), we discovered that the aryl urea 1 is a modestly potent yet nonselective inhibitor. Structure-activity relationship studies revealed that adding substituents to the nitrogen atom of the urea so as to generate compounds bearing a branched linker group results in increased potency and selectivity for HDAC6. Compound 5 g shows low nanomolar inhibitory potency against HDAC6 and a selectivity of ∼600-fold relative to the inhibition of HDAC1. These HDACIs were evaluated for their ability to inhibit the growth of B16 melanoma cells with the most potent and selective HDAC6I being found to decrease tumor cell growth. To the best of our knowledge, this work constitutes the first report of HDAC6-selective inhibitors that possess antiproliferative effects against melanoma cells.
近年来，恶性黑色素瘤的发病率显著上升，因此需要改进治疗策略。在我们设计选择性组蛋白去乙酰化酶抑制剂（HDACI）的过程中，我们发现芳基脲 1 是一种中等强度但非选择性的抑制剂。构效关系研究表明，在脲的氮原子上引入取代基，生成带有支链连接基团的化合物，可提高对 HDAC6 的活性和选择性。化合物 5g 对 HDAC6 具有低纳摩尔抑制活性，对 HDAC1 的选择性约为 600 倍。这些 HDACI 的抗肿瘤细胞生长能力进行了评估，发现活性最强和选择性最高的 HDAC6I 能够降低肿瘤细胞的生长。据我们所知，这是首次报道具有抗黑色素瘤细胞增殖作用的 HDAC6 选择性抑制剂。
